Ofatumumab Cardiac Repolarization (QTc) Study in Fludarabine-Refractory Chronic Lymphocytic Leukemia Subjects

An Open-Label, Single-Arm, Phase I Study to Evaluate the Effect of Ofatumumab on Cardiac Repolarization (QTc Duration) in Patients With Fludarabine-Refractory B-cell Chronic Lymphocytic Leukemia

Ofatumumab is a fully-human monoclonal antibody that exhibits high binding affinity to an antigen on the surface of B lymphocytes. Antigen engagement by ofatumumab results in maximal B-cell killing through complement-dependent cytotoxicity and antigen-dependent cellular cytotoxicity in both antigen high- and low-expressing cells. Recent research has shown that ofatumumab-dependent B-cell depletion provides clinical benefit to subjects with CD20-positive cancers such as chronic lymphocytic leukemia (CLL). The purpose of the current study is to assess the impact of ofatumumab on electrocardiographic parameters with particular focus on cardiac repolarization (QTc interval duration) in subjects with refractory CLL. Subjects enrolled in this open-label, single-arm trial will receive ofatumumab at the highest clinical dose (2000 mg) studied or planned for study. Ofatumumab will be administered as eight weekly intravenous (IV) infusions followed by four monthly infusions, beginning in Week 13, across a 25-week treatment period. Cardiovascular effects will be evaluated during treatment through routine 12-lead electrocardiographic (ECG) monitoring. The pharmacokinetic relationship between plasma concentration of ofatumumab and its effect on QTc interval duration will be examined. Specifically, ECG assessments will be collected in triplicate at baseline, at the time of maximum ofatumumab concentrations periodically on-therapy, and at the end of treatment. After completion of the final ofatumumab infusion, subjects will continue to be followed for safety and efficacy for six months relative to the last ofatumumab dose.

Study Overview

• Status: Completed
• Conditions: Leukaemia, Lymphocytic, Chronic
• Intervention / Treatment: Biological: Ofatumumab

Detailed Description

The purpose of this trial is to assess the impact of ofatumumab on electrocardiographic parameters with particular focus on cardiac repolarization (QTc interval duration) in subjects with refractory Chronic Lymphocytic Leukemia (CLL).

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Randwick, New South Wales, Australia, 2031
      • GSK Investigational Site
• New Zealand
  • Auckland, New Zealand, 1150
    • GSK Investigational Site
  • Christchurch, New Zealand, 8011
    • GSK Investigational Site
• United States
  • California
    • La Jolla, California, United States, 92093
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Confirmed diagnosis of Chronic Lymphocytic Leukemia (CLL).
• Active CLL disease and indication for treatment.
• Previous treatment with fludarabine-containing treatment that did not achieve at least a partial response or, disease progression occurred in responders within six months of the last dose of a fludarabine-containing treatment regimen.
• Fully active at a minimum, or fully capable of self-care and up and about more than 50% of waking hours.
• Age 18 years or older.
• Signed written informed consent.
• Acceptable levels of laboratory chemistry tests of potassium and magnesium.
• Males and female subjects must agree to use contraception (if fertile) from the time of the first dose of study medication until one year following last dose of ofatumumab.

Exclusion Criteria:

• Any abnormal electrocardiogram (ECG) or cardiac conduction findings .
• Certain heart problems, chronic infections, or serious significant diseases.
• Known transformation of CLL.
• CLL central nervous sytem involvement.
• Abnormal/inadequate blood values, liver, or kidney function.
• Past or current malignancy besides CLL, unless you have been free of malignancy for at least two years, have a history of completely resected non-melanoma skin cancer, or have been successfully treated.
• Lactating women or women with a positive pregnancy test.
• Use of medications known to prolong the heart rhythm.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment; Six months treatmet with ofatumumab will be given to subjects with chronic lymphocytic leukemia.	Biological: Ofatumumab; Anti-CD20 monoclonal antibody; Other Names: Arzerra

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cardiac Repolarization (Fredericia's QTc)	ECGs are collected in triplicate during the study to assess QTc effect.	25-week ofatumumab treatment period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma concentrations of ofatumumab and electrocardiogram (ECG) parameters	The pharmacokinetic results will be correlated to ECG findings to determine if drug concentrations relate to any ECG effects.	25-week ofatumumab treatment period
Vital signs, weight, adverse events	Safety and tolerability of ofatumumab therapy will be determined by analysing changes in vital signs, weight, or development of adverse events.	25-week ofatumumab treatment period plus 6-month follow-up after final ofatumumab infusion
Flow cytometry	Efficacy of ofatumumab therapy will be measured by the number of CD20 positive cells in the blood	25-week ofatumumab treatment period plus 6-month follow-up after final ofatumumab infusion
Cytokine, chemokine, human anti-human antibodies	Effect of ofatumumab on circulating biomarkers in refractory Chronic Lymphocytic Leukemia (CLL) subjects will be determined by measuring changes in the cytokine, chemokine, human anti-human antibody levels.	25-week ofatumumab treatment period plus 6-month follow-up after final ofatumumab infusion

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Publications and helpful links

General Publications

• Jewell RC, Laubscher K, Lewis E, Fang L, Gafoor Z, Carey J, McKeown A, West S, Wright O, Sedoti D, Dixon I, Hottenstein CS, Chan G. Assessment of the effect of ofatumumab on cardiac repolarization. J Clin Pharmacol. 2015 Jan;55(1):114-21. doi: 10.1002/jcph.376. Epub 2014 Aug 21.

Study record dates

Study Major Dates

• Study Start (Actual): May 13, 2010
• Primary Completion (Actual): April 12, 2012
• Study Completion (Actual): June 26, 2012

Study Registration Dates

• First Submitted: April 22, 2010
• First Submitted That Met QC Criteria: April 22, 2010
• First Posted (Estimate): April 23, 2010

Study Record Updates

• Last Update Posted (Actual): November 13, 2017
• Last Update Submitted That Met QC Criteria: November 8, 2017
• Last Verified: November 1, 2017

More Information

Terms related to this study

• Keywords: Chronic lymphocytic leukemia; Cardiac Repolarization (QTc)
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia, B-Cell; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Antineoplastic Agents; Ofatumumab
• Other Study ID Numbers: 112855